The metabolic syndrome, a constellation of metabolic and cardiovascular anomalies that heavily impact the morbidity and mortality of obese individuals, frequently complicates successful treatment for obesity. Obesity- associated insulin resistance plays a central role in the pathogenesis of the metabolic syndrome, and insulin signaling is an important focus in obesity research. Several protein tyrosine phosphatases recently emerged as critical negative regulators of insulin signaling and quickly became popular targets of drug development efforts for obesity and type 2 diabetes. This grant focuses on a tyrosine phosphatase called the low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the Acp1 gene. The LMPTP is highly expressed in insulin- target tissues and several data suggest it is a negative regulator of insulin signaling in vitro and in vivo. Multiple lines of evidence support an important role of LMPTP in modulating glucose and lipid metabolism in obesity. Recent in vivo data obtained using antisense oligonucleotides showed that knockdown of LMPTP reverses insulin resistance and lipid abnormalities in obese mice. Thus LMPTP appears to be a promising drug target for the metabolic syndrome. We hypothesize that a specific small-molecule inhibitor of the LMPTP can be useful to prevent or treat the metabolic complication of obesity. Such an inhibitor would be widely applicable, both in helping to elucidate the biological role(s) of LMPTP and as a therapeutic in the treatment of the metabolic syndrome. In the present proposal we will screen the NIH chemical library for inhibitors of LMPTP, and generate a potent and selective probe that can be used in studies on mouse models of the metabolic syndrome.